Evidence Report/Technology Assessment Number 89

Transcription

1 Evidence Report/Technology Assessment Number 89 Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD Contract No Prepared by: Southern California/RAND Evidence-based Practice Center, Los Angeles, CA Program Directors Paul G. Shekelle, MD, PhD Sally C. Morton, PhD Project Director Catherine H. MacLean, MD, PhD Project Manager Rena Hasenfeld Garland, BA Statistician Wenli Tu, MS Programmer/Analyst Lara K. Jungvig, BA Scientific Reviewers Walter A. Mojica, MD, MPH James Pencharz, BSc (Kin) Jennifer Grossman, MD Puja Khanna, MD, MPH Editor Sydne J. Newberry, PhD Technical Advisors Ian Gralnek, MD, MSHS Alan Nissenson, MD Librarians Jessie McGowan, MLIS Nancy Santesso, RD, MLIS Staff Assistants Donna Mead, BA Shannon Rhodes, MFA Shana Traina, MA AHRQ Publication No. 04-E012-2 March 2004

2 This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers patients and clinicians, health system leaders, and policymakers make more informed decisions and improve the quality of health care services.

3 This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders. Suggested Citation: MacLean CH, Mojica, WA, Morton SC, Pencharz J, Hasenfeld Garland R, Tu W, Newberry SJ, Jungvig LK, Grossman J, Khanna P, Rhodes S, Shekelle P. Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis. Evidence Report/Technology Assessment. No. 89 (Prepared by Southern California/RAND Evidence-based Practice Center, under Contract No ). AHRQ Publication No. 04-E Rockville, MD: Agency for Healthcare Research and Quality. March ii

4 Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. This report on Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis was requested and funded by the Office of Dietary Supplements, National Institutes of Health, through the EPC Program at the Agency for Healthcare Research and Quality. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments. To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release. AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality. We welcome written comments on this evidence report. They may be sent to: Director, Center for Outcomes and Evidence, Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD Carolyn M. Clancy, M.D. Director Agency for Healthcare Research and Quality Paul Coates, Ph.D. Director, Office of Dietary Supplements National Institutes of Health Jean Slutsky, P.A., M.S.P.H. Acting Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service. iii

5 Acknowledgments We thank Herbert D. Woolf, PhD, of BASF Corporation for providing us with unpublished data on omega-3 fatty acids. We thank Antonio LaCava, MD, PhD for providing translation of Italian studies, Takahiro Higashi, MD for providing translation of Japanese studies, Markus Rihl, MD for providing translation of German studies, and Anna Maria Björnsdotter, BA, for providing translation of Swedish studies. Chapter 1 was written in collaboration with the Tufts-New England Medical Center Evidence-based Practice Center. iv

6 Structured Abstract Context: Clinical trials report differing effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease (IBD), rheumatic arthritis, renal disease, systemic lupus erythemosus (SLE), and osteoporosis. Objectives: To assess the effect of omega-3 fatty acids on 1) total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and insulin resistance in type-ii diabetes and the metabolic syndrome, 2) clinical score, sigmoidoscopic score, histologic score and requirement for immunosuppressive therapy in IBD, 3) pain, swollen and tender joint counts, acute phase reactants, patient global assessment, and requirement for anti-inflammatory or immunosuppressive therapy in rheumatoid arthritis, 4) renal function, progression to end-stage renal disease, hemodialysis graft patency, mortality, and requirement for immunosuppressive therapy in renal disease, 5) disease activity, damage, patient s perception of disease activity, and requirement for immunosuppressive therapy in SLE, and 6) bone mineral density and fracture rates. Data Sources: We searched on-line databases to identify potentially relevant studies and contacted industry experts for unpublished data. Study Selection: We screened 4,212 titles, reviewed 1,097 articles, and included 83 articles. We restricted to randomized controlled trials (RCTs), but included case-control and cohort studies for bone/fracture. We had no language restrictions. Data Extraction: We abstracted data on study design, study population, and outcomes; source, amount, and duration of omega-3 fatty acid consumption; and randomization, dropouts, blinding, and allocation for RCTs. Data Synthesis: We performed meta-analyses for diabetes, rheumatoid arthritis, and IBD; and qualitative analyses for the other conditions. For diabetes, omega-3 fatty acids had a favorable effect on triglyceride levels but no significant effect on total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood sugar, or glycosylated hemoglobin. There was no effect on plasma insulin or insulin resistance in type II diabetics or the metabolic syndrome. For IBD, omega-3 fatty acids had variable effects on clinical score, sigmoidoscopic score, histologic score, induced remission, and relapse, and no effect on the relative risk of relapse in ulcerative colitis. There was a statistically non-significant reduction in requirement for corticosteroids. No studies evaluated requirement for other immunosuppressive agents. For rheumatoid arthritis, omega-3 fatty acids had no effect on patient report of pain, swollen joint count, Erythrocyte Sedimentation Rate, and patient s global assessment. There was no effect on joint damage, contrary to a previous meta-analysis. There was a reduced requirement for anti-inflammatory drugs or corticosteroids. No studies assessed requirements for disease modifying antirheumatic drugs. For renal disease, omega-3 fatty acids had varying effects on serum creatinine and creatinine clearance. Single studies respectively demonstrated reduced progression to end-stage renal disease and improvements on hemodialysis graft patencyrelative. No studies assessed requirements for corticosteroids or other immunosuppressive drugs. v

7 For SLE, omega-3 fatty acids had variable effects on clinical activity. No studies assessed the effect on end organ damage, patient perception of disease, or requirements for other immunosuppressive drugs. One study showed no effect on corticosteroid requirements. For bone mineral density, the effect of omega-3 fatty acids was variable. No studies assessed the effect on fracture. Conclusions: The evidence for effects of omega-3 fatty acids on outcomes in the conditions assessed varies greatly. Omega-3 fatty acids appear to reduce serum triglycerides among type II diabetics, but have no effect on total cholesterol, HDL cholesterol, and LDL cholesterol. There appears to be no effect on most clinical outcomes in rheumatoid arthritis, although tender joint count may be reduced. There are insufficient data to draw conclusions about IBD, renal disease, SLE, bone density or fractures, requirement for anti-inflammatory or immunosuppressive drugs, or insulin resistance among type II diabetics. vi

8 Contents Evidence Report Chapter 1. Introduction... 1 The Recognition of Essential Fatty Acids... 1 Fatty Acid Nomenclature... 1 Fatty Acid Metabolism... 2 Physiological Functions of EPA and AA... 3 Dietary Sources and Requirements... 4 Rationale for and Organization of this Report... 9 Chapter 2. Methodology...11 Objectives...11 Scope of Work...11 Original Proposed Key Question...11 Technical Expert Panel...12 Key Questions Addressed in this Report...12 Diabetes...12 Inflammatory Bowel Disease...13 Rheumatoid Arthritis...13 Renal Disease...14 Systemic Lupus Erythematosus...14 Bone Density/Osteoporosis...14 Assessment of Adverse Events...14 Identification of Literature Sources...15 Evaluation of Evidence...16 Extraction of Data...16 Grading Evidence...16 Methodologic Quality of Randomized Controlled Trials...16 Applicability...17 Data Synthesis...17 Meta-Analysis...17 Selection of Trials for Descriptive Analysis or Meta-Analysis...17 Trial Summary Statistics...18 Stratification of Trials...19 Performance of Meta-Analysis...19 Sensitivity Analysis...19 Publication Bias...20 Interpretation of the Results...20 Peer Review...20 Chapter 3. Results...21 Results of Literature Search Diabetes Diabetes: Total Cholesterol vii

9 Diabetes: HDL Cholesterol Diabetes: LDL Cholesterol Diabetes: Triglycerides Diabetes: Insulin Sensitivity/Glycemic Control Inflammatory Bowel Disease Inflammatory Bowel Disease: Clinical Effect Inflammatory Bowel Disease: Effect on Requirement for Steroids/Other Immunosuppresive Drugs Rheumatoid Arthritis Rheumatoid Arthritis: Pain Rheumatoid Arthritis: Swollen Joints Rheumatoid Arthritis: Disease Activity (ESR) Rheumatoid Arthritis: Patient s Global Assessment Rheumatoid Arthritis: Joint Damage Rheumatoid Arthritis: Tender Joint Count Rheumatoid Arthritis: Effect on Anti-Inflammatory/Immunosuppressive Drug Requirement Renal Disease Renal Disease: Clinical Effect Renal Disease: Effect on Corticosteroid/Other Immunosuppressive Drug Requirement Systemic Lupus Erythematosus Systemic Lupus Erythematosus: Clinical Effect Systemic Lupus Erythematosus: Effect on Steroid/Other Immunosuppressive Drug Requirement Bone Density/Osteoporosis Bone Density/Osteoporosis: Clinical Effect Publication Bias Adverse Events Chapter 4. Discussion Overview..61 Main Findings..61 Conclusions..63 Future Research 63 References and Included Studies Listing of Excluded Studies Acronyms Tables Table 1.1 Nomenclature of Omega-3 Fatty Acids...2 viii

10 Table 1.2 Sources and Proportions of Omega-3 Fatty Acids in Common Foods and Supplements...6 Table 1.3 Good Food Sources of Omega-3 Fatty Acids...7 Table 1.4 Estimates of the Mean Intake of LA, ALA, EPA, and DHA in the U.S. Population from Analysis of NHANES III Data...8 Table 1.5 Mean, Range, and Median Usual Daily Intakes (Ranges) of n-6 and n-3 PUFAs in the U.S. Population, from Analysis of CSFII Data (1994 to 1998)...8 Table 1.6 The Omega-3 Fatty Acid Content, in Grams per 100 g Food Serving, of a Representative Sample of Commonly Consumed Fish, Shellfish, and Fish Oils, and Nuts and Seeds, and Plant Oils that Contain at Least 5 g Omega-3 Fatty Acids per 100 g...10 Table 3.1 Diabetes: Mean Difference for Total Cholesterol...24 Table 3.2 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Total Cholesterol among People with Type II Diabetes...24 Table 3.3 Diabetes: Mean Difference for High-Density Lipoprotein (HDL)...27 Table 3.4 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on HDL among People with Type II Diabetes...27 Table 3.5 Diabetes: Mean Difference for Low-Density Lipoprotein (LDL)...30 Table 3.6 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on LDL among People with Type II Diabetes...30 Table 3.7 Diabetes: Mean Difference for Triglycerides...33 Table 3.8 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Triglycerides among People with Type II Diabetes...33 Table 3.9 Diabetes: Mean Difference of Fasting Blood Glucose...36 Table 3.10 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Fasting Blood Sugar among People with Type II Diabetes...37 Table 3.11 Diabetes: Effect Size of Hemoglobin A1c (HbA1c)...38 Table 3.12 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Glycosylated Hemoglobin among People with Type II Diabetes...38 Table 3.13 Ulcerative Colitis Disease: Relative Risk of Relapse...41 Table 3.14 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption with Ulcerative Colitis Disease for Relapse/Remission...42 Table 3.15 RA: Effect Size for Patient Assessment of Pain...44 Table 3.16 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Pain among People with Rheumatoid Arthritis...45 Table 3.17 RA: Effect Size for Swollen Joint Count...47 ix

11 Table 3.18 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Swollen Joints among People with Rheumatoid Arthritis...47 Table 3.19 RA: Effect Size for ESR...50 Table 3.20 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption of ESR among People with Rheumatoid Arthritis...51 Table 3.21 RA: Effect Size for Patient Global Assessment...53 Table 3.22 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Global Assessment among People with Rheumatoid Arthritis...53 Table 3.23 Summary of Reported Adverse Events...59 Figures Figure 1.1 Classical Omega-3 and Omega-6 Fatty Acid Synthesis Pathways and the Role of Omega-3 Fatty Acid in Regulating Health/Disease Markers...5 Figure 3.1 Literature Flow...22 Figure 3.2 Diabetes: Total Cholesterol...25 Figure 3.3 Diabetes: High Density Lipoprotein (HDL)...28 Figure 3.4 Diabetes: Low Density Lipoprotein (LDL)...31 Figure 3.5 Diabetes: Triglycerides...34 Figure 3.6 Diabetes: Fasting Blood Glucose...37 Figure 3.7 Diabetes: Hemoglobin A1c (HgA1c)...39 Figure 3.8 Ulcerative Colitis Disease: Relative Risk of Relapse...42 Figure 3.9 RA: Patient Assessment of Pain...45 Figure 3.10 RA: Swollen Joint Count...48 Figure 3.11 RA: ESR...51 Figure 3.12 RA: Patient Global Assessment...54 Appendices and Evidence Tables are provided electronically at x

12 Agency for Healthcare Research and Quality Evidence Report/Technology Assessment Number 89 Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis Summary Introduction This report was requested and funded by the Office of Dietary Supplements, National Institutes of Health. It is one of several reports focusing on the role of omega-3 fatty acids in the prevention or treatment of various diseases. Three Evidence-based Practice Centers (EPCs) produced this series of reports: the Southern California EPC, based at RAND, the Tufts-New England Medical Center EPC, and the University of Ottawa EPC. This particular report focuses on the effects of omega-3 fatty acids on immunemediated diseases, bone metabolism, and gastrointestinal/renal diseases. Over the past 40 years, an increasing number of physiological functions have been attributed to omega-3 fatty acids, including movement of calcium and other substances into and out of cells, relaxation and contraction of muscles, inhibition and promotion of clotting, regulation of secretion of substances that include digestive enzymes and hormones, control of fertility, cell division, and growth. 1 In addition, omega-3 fatty acids may play an important role in brain development and function. Some evidence has suggested that omega-3 fatty acids in the diet may protect against heart attack and stroke, as well as certain inflammatory diseases like arthritis, lupus, and asthma. 1 The major dietary sources of omega- 3 fatty acids in the U.S. population are fish, fish oil, vegetable oils (principally canola and soybean), walnuts, wheat germ, and some dietary supplements. Methods Key Questions We consulted with three technical expert panels (TEPs) on this project. The respective panels focused on the following conditions: Rheumatoid arthritis, systemic lupus erythematosis (SLE), and bone density/osteoporosis Renal disease and diabetes Gastrointestinal diseases The TEPs advised us on refining the preliminary questions posed to us by AHRQ, determining the proper inclusion/exclusion criteria for the study and the populations of interest, establishing the proper outcomes measures, and conducting the appropriate analyses. Based on the original questions that we received from AHRQ and input from our TEPs, we addressed the following questions in this study: Diabetes What is the evidence in adults or children with a) type II diabetes, or b) insulin resistance/the metabolic syndrome for an effect of omega-3 fatty acids on: Total cholesterol HDL cholesterol LDL cholesterol Triglycerides U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

13 What is the evidence in adults and children for an effect of omega-3 fatty acids on insulin sensitivity in a) type II diabetes, or b) the metabolic syndrome? Inflammatory Bowel Disease What is the evidence for the efficacy of omega-3 fatty acids in treatment of Crohn s disease and ulcerative colitis? What is the evidence in adults or children with inflammatory bowel disease that omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of inflammatory bowel disease? Rheumatoid Arthritis What is the evidence in adults or children with rheumatoid arthritis that omega-3 fatty acids affect: Pain Number of swollen joints Disease activity Patients global assessment Joint damage What is the evidence in adults or children with rheumatoid arthritis that omega-3 fatty acids can replace other more potent anti-inflammatory or immunosuppressive drugs such as steroids and nonsteroidal anti-inflammatory drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of rheumatoid arthritis? Renal Disease What is the evidence for the efficacy of omega-3 fatty acids in treatment of renal inflammation and glomerulosclerosis? What is the evidence in adults or children with immunemediated renal disease that omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of immunemediated renal disease? Systemic Lupus Erythematosus What is the evidence in adults or children with SLE that omega-3 fatty acids affect disease activity, damage, or patient perceptions of outcomes in SLE? What is the evidence in adults or children with SLE that omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids in the treatment of SLE are influenced by the concomitant administration of various immunosuppressive agents? Bone Density/Osteoporosis What is the evidence that omega-3 fatty acids help maintain bone mineral status? For each of the study questions, we also assessed: The effect of omega-3 fatty acids on subpopulations The effects of covariates, dose, source, and exposure duration on the outcomes of interest The sustainment of effect In addition to answering these questions, we evaluated the data on adverse events, including clinical bleeding, gastrointestinal complaints or nausea, diarrhea, headache, dermatological problems, and withdrawal from study due to an adverse event. Search Strategy We searched the following online databases to identify literature: MEDLINE (1966-July 2003), PreMEDLINE (July 8, 2003), EMBASE (1980-Week 27, 2003), Cochrane Central Register of Controlled Trials (2nd Quarter, 2003), CAB Health (1973-June 2003), and Dissertation Abstracts (1861-December 2002). We developed a core search strategy and applied it to each relevant disease category: rheumatoid arthritis, bone density, SLE, renal disease, diabetes, and gastrointestinal diseases. We also reviewed the reference lists of all applicable articles and contacted our technical expert panel as well as industry experts to identify unpublished data. Selection Criteria Two reviewers independently reviewed each article considered for inclusion in the study. Any disagreements between the reviewers were resolved through consensus. We included any articles pertaining to the effects of omega-3 fatty acids on diabetes mellitus, inflammatory bowel disease (ulcerative colitis and Crohn s disease), rheumatoid arthritis, SLE, renal disease, osteoporosis, or bone mineral status. We included only articles that presented research on human subjects and those that reported the results of randomized clinical trials or controlled clinical trials; we accepted observational studies only for bone mineral status. Language was not a barrier to inclusion. Data Extraction and Analysis For each article included in the study, two reviewers independently extracted data about the trial design; the outcomes of interest; the quality of the trial; the number and characteristics of the patients; details on the intervention, such 2

14 as the dose, frequency, and duration; the types of outcome measures; adverse events; and the elapsed time between the intervention and outcome measurements. Any disagreements between the reviewers were resolved through consensus. For each article, we then evaluated the quality of the design and execution of trials using a system developed by Jadad; determined a combined applicability grade based on applicability to the U.S. population and health state; performed a meta-analysis of those studies that sufficiently assessed interventions, populations, and outcomes to justify pooling; and performed a qualitative analysis of the remaining studies. Results We screened 4,212 article titles. From these article titles, we reviewed the 1,097 full-text articles relevant to our topics. Of these full-text articles, 115 met our selection criteria and underwent detailed review; among these, 83 articles met our inclusion criteria (34 for diabetes/metabolic syndrome, 13 for inflammatory bowel disease, 21 for rheumatoid arthritis, 9 for renal disease, 3 for SLE, and 4 for bone density and fractures). All of these 83 articles were randomized controlled trials, except for one observational study of bone density. We had a sufficient number of articles to perform quantitative meta-analyses for rheumatoid arthritis, inflammatory bowel disease, and diabetes. Due to the limited number of articles we identified for renal failure, SLE, and bone mineral metabolism, we performed qualitative analyses for these conditions. Overall, our analyses yielded variable results both within and among disease categories. Our findings are summarized for each condition studied. Diabetes/Metabolic Syndrome. Among 18 studies of type II diabetes or the metabolic syndrome, omega-3 fatty acids had a favorable effect on triglyceride levels relative to placebo (pooled random effects estimate: ; 95% CI, , ) but had no effect on total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood sugar, or glycosylated hemoglobin, by meta-analysis. Omega-3 fatty acids had no effect on plasma insulin or insulin resistance in type II diabetics or patients with the metabolic syndrome, by qualitative analysis of four studies. Inflammatory Bowel Disease. Among 13 studies reporting outcomes in patients with inflammatory bowel disease, variable effects of omega-3 fatty acids on clinical score, sigmoidoscopic score, histologic score, induced remission, and relapse were reported. In ulcerative colitis, omega-3 fatty acids had no effect on the relative risk of relapse in a meta-analysis of three studies. There was a statistically non-significant reduction in requirement for corticosteroids for omega-3 fatty acids relative to placebo in two studies. No studies evaluated the effect of omega-3 fatty acids on requirement for other immunosuppressive agents. Rheumatoid Arthritis. Among nine studies reporting outcomes in patients with rheumatoid arthritis, omega-3 fatty acids had no effect on patient report of pain, swollen joint count, Erythrocyte Sedimentation Rate (ESR), and patient s global assessment by meta-analysis. A previously performed meta-analysis 2 reached the same conclusions for swollen joint count, ESR, and patient s global assessment. That metaanalysis found a statistically significant improvement in tender joint count compared to placebo (rate difference = -2.9, 95% CI, -3.8, -2.1). The one study that assessed the effect on joint damage found no effect. In a qualitative analysis of seven studies that assessed the effect of omega-3 fatty acids on antiinflammatory drug or corticosteriod requirement, six demonstrated reduced requirement for these drugs. No studies assessed the effect on requirements for disease modifying antirheumatic drugs. None of the studies used a composite score that incorporates both subjective and objective measures of disease activity, such as the American College of Rheumatology response criteria. Renal Disease. In a qualitative analysis of nine studies that assessed the effect of omega-3 fatty acids in renal disease, there were varying effects on serum creatinine and creatinine clearance and no effect on progression to end stage renal disease. In a single study that assessed the effect on hemodialysis graft patency, graft patency was significantly better with fish oil than with placebo. No studies assessed the effects of omega-3 fatty acids on requirements for corticosteroids Systemic Lupus Erythematosis. Among three studies that assessed the effects of omega-3 fatty acids in SLE, variable effects on clinical activity were reported. No studies were identified that assessed effect on damage or patient perception of disease. Omega-3 fatty acids had no effect on corticosteroid requirements in one study. No studies were identified that assessed the effects of omega-3 fatty acids on requirements for other immunosuppressive drugs for SLE. None of the studies used a measure of disease activity that incorporates both subjective and objective measures of disease activity. Bone Mineral Density/Fracture. Among five studies described in four reports the effect of omega-3 fatty acids on bone mineral density was variable. No studies that assessed the effect of omega-3 fatty acids on fracture were identified. The quantity and strength of evidence for effects of omega-3 fatty acids on outcomes in the conditions assessed varies greatly. The findings of many studies among type II diabetics provide strong evidence that omega-3 fatty acids reduce serum triglycerides but have no effect on total cholesterol, HDL cholesterol, and LDL cholesterol. For rheumatoid arthritis, the available evidence suggests that omega-3 fatty acids reduce tender joint counts and may reduce requirements for corticosteroids, but does not support an effect of omega-3 fatty acids on other clinical outcomes. There are insufficient data available to draw conclusions about the effects of omega-3 fatty 3

15 acids on inflammatory bowel disease, renal disease, SLE, bone density, or fractures or the effects of omega-3 fatty acids on insulin resistance among type II diabetics. Discussion We offer the following observations and recommendations regarding future research on the effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, SLE, and osteoporosis. Additional research on the effects of omega-3 fatty acids needs to be performed on inflammatory bowel disease, renal disease, SLE, bone density, or fractures or the effects of omega-3 fatty acids on insulin resistance among type II diabetics before recommendations regarding the use of omega-3 fatty acids for these conditions can be made. Studies of inflammatory bowel disease that include patients with both Crohn s disease and ulcerative colitis should report data separately for these groups. Studies that assess the effects of omega-3 fatty acids should use standard validated instruments to assess clinical outcomes. Trials that assess the effects of omega-3 fatty acids should be designed to evaluate the effect of source, dose, treatment duration, and the sustainment of effect after discontinuation of omega-3 fatty acid consumption. Studies of omega-3 fatty acids should explicitly define both the quantity of the omega-3 fatty acid source and of the specific omega-3 fatty acids present in a study dose of that source. Trials of omega-3 fatty acids should include a baseline assessment of dietary omega-3 and omega-6 fatty acid intake. In controlled trials that assess the effects of omega-3 fatty acids, analysis should include and report explicit testing of the effects of the omega-3 fatty acid relative to the control substance. In studies that use a crossover design, outcome data for all study arms should be reported at the end of each treatment period. Availability of the Full Report The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the Southern California/RAND Evidencebased Practice Center, Los Angeles, CA, under Contract No The full report is expected to be available in March At that time, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling Requesters should ask for Evidence Report/Technology Assessment No. 89, Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis. In addition, Internet users will be able to access the report and this summary online through AHRQ s Web site at Suggested Citation MacLean CH, Mojica WA, Morton SC, Pencharz J, Hasenfeld Garland R, Tu W, Newberry SJ, Jungvig LK, Grossman J, Khanna P, Rhodes S, Shekelle P. Effects of Omega- 3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis. Summary, Evidence Report/Technology Assessment No. 89. (Prepared by the Southern California/RAND Evidence-based Practice Center, Los Angeles, CA.) AHRQ Publication No. 04-E Rockville, MD: Agency for Healthcare Research and Quality. March References 1. Innis S. Essential dietary lipids. In: Ziegler EE, Filer, LJ Jr, editors. Present knowledge in nutrition. Washington, DC: International Life Sciences Institute; Fortin P, Lew R, Liang M, et al. Validation of a meta-analysis: The effects of fish oil in rheumatoid arthritis. J Clin Epidemiol 1995;48(11): AHRQ Pub. No. 04-E012-1 March 2004 ISSN X

16 Evidence Report

17 Chapter 1. Introduction This report is one of a group of evidence reports prepared by three Agency for Healthcare Research and Quality (AHRQ)-funded Evidence-Based Practice Centers (EPCs) on the role of omega-3 fatty acids (both from food sources and from dietary supplements) in the prevention or treatment of a variety of diseases. These reports were requested and funded by the Office of Dietary Supplements, National Institutes of Health. The three EPCs the Southern California EPC (SCEPC, based at RAND), the Tufts-New England Medical Center (NEMC) EPC, and the University of Ottawa EPC have each produced evidence reports. To ensure consistency of approach, the three EPCs collaborated on selected methodological elements, including literature search strategies, rating of evidence, and data table design. The aim of these reports is to summarize the current evidence on the effects of omega-3 fatty acids on prevention and treatment of cardiovascular diseases, cancer, child and maternal health, eye health, gastrointestinal/renal diseases, asthma, immune-mediated diseases, tissue/organ transplantation, mental health, and neurological diseases and conditions. In addition to informing the research community and the public on the effects of omega-3 fatty acids on various health conditions, it is anticipated that the findings of the reports will also be used to help define the agenda for future research. This report focuses on the effects of omega-3 fatty acids on immune-mediated diseases, bone metabolism, and gastrointestinal/renal diseases. Subsequent reports from the SCEPC will focus on cancer and neurological diseases and conditions. This chapter provides a brief review of the current state of knowledge about the metabolism, physiological functions, and sources of omega-3 fatty acids. The Recognition of Essential Fatty Acids Dietary fat has long been recognized as an important source of energy for mammals, but in the late 1920s, researchers demonstrated the dietary requirement for particular fatty acids, which came to be called essential fatty acids. It was not until the advent of intravenous feeding, however, that the importance of essential fatty acids was widely accepted: Clinical signs of essential fatty acid deficiency are generally observed only in patients on total parenteral nutrition who received mixtures devoid of essential fatty acids or in those with malabsorption syndromes. These signs include dermatitis and changes in visual and neural function. Over the past 40 years, an increasing number of physiological functions, such as immunomodulation, have been attributed to the essential fatty acids and their metabolites, and this area of research remains quite active. 1, 2 Fatty Acid Nomenclature The fat found in foods consists largely of a heterogeneous mixture of triacylglycerols (triglycerides)--glycerol molecules that are each combined with three fatty acids. The fatty acids can be divided into two categories, based on chemical properties: saturated fatty acids, which are usually solid at room temperature, and unsaturated fatty acids, which are liquid at room Note: Appendixes and Evidence Tables are provided electronically at 1

18 temperature. The term saturation refers to a chemical structure in which each carbon atom in the fatty acyl chain is bound to (saturated with) four other atoms, these carbons are linked by single bonds, and no other atoms or molecules can attach; unsaturated fatty acids contain at least one pair of carbon atoms linked by a double bond, which allows the attachment of additional atoms to those carbons (resulting in saturation). Despite their differences in structure, all fats contain approximately the same amount of energy (37 kilojoules/gram, or 9 kilocalories/gram). The class of unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids. Monounsaturated fatty acids (the primary constituents of olive and canola oils) contain only one double bond. Polyunsaturated fatty acids (PUFAs) (the primary constituents of corn, sunflower, flax seed and many other vegetable oils) contain more than one double bond. Fatty acids are often referred to using the number of carbon atoms in the acyl chain, followed by a colon, followed by the number of double bonds in the chain (e.g., 18:1 refers to the 18-carbon monounsaturated fatty acid, oleic acid; 18:3 refers to any 18-carbon PUFA with three double bonds). PUFAs are further categorized on the basis of the location of their double bonds. An omega or n notation indicates the number of carbon atoms from the methyl end of the acyl chain to the first double bond. Thus, for example, in the omega-3 (n-3) family of PUFAs, the first double bond is 3 carbons from the methyl end of the molecule. The trivial names, chemical names and abbreviations for the omega-3 fatty acids are detailed in Table 1.1. Finally, PUFAs can be categorized according to their chain length. The 18-carbon n-3 and n- 6 short-chain PUFAs are precursors to the longer 20- and 22-carbon PUFAs, called long-chain PUFAs (LCPUFAs). Table 1.1. Nomenclature of omega-3 fatty acids. Names Abbreviations Trivial IUPAC* Carboxyl-reference Omega-reference Other Linolenic acid 9,12,15-octadecenoic acid 18: :3n-3 18:3 (ω-3) ALA α-la LNA α-lna Docosahexaenoic acid 4,8,12,15,19- docosahexaenoic 22: :6n-3 DHA acid 22:6 (ω-3) Docosapentaenoic acid 7,10,13,16,19- docosapentaenoic acid 22: :5n-3 22:5 (ω-3) DPA Eicosapentaenoic acid Icosapentaenoic acid Timnodonic acid 5,8,11,14,17- eicosapentaenoic acid *IUPAC=International Union of Pure and Applied Chemistry 20: :5n-3 20:5 (ω-3) EPA Fatty Acid Metabolism Mammalian cells can introduce double bonds into all positions on the fatty acid chain except the n-3 and n-6 position. Thus, the short-chain alpha-linolenic acid (ALA, chemical abbreviation: 18:3n-3) and linoleic acid (LA, chemical abbreviation: 18:2n-6) are essential fatty acids. No other fatty acids found in food are considered essential for humans, because they can all be synthesized from the short chain fatty acids. 2

19 Following ingestion, ALA and LA can be converted in the liver to the long chain, moreunsaturated n-3 and n-6 LCPUFAs by a complex set of synthetic pathways that share several enzymes (Figure 1). LC PUFAs retain the original sites of desaturation (including n-3 or n-6). The omega-6 fatty acid LA is converted to gamma-linolenic acid (GLA, 18:3n-6), an omega- 6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the longerchain omega-6 fatty acid, arachidonic acid (AA, 20:4n-6). AA is the precursor for certain classes of an important family of hormone-like substances called the eicosanoids (see below). The omega-3 fatty acid ALA (18:3n-3) can be converted to the long-chain omega-3 fatty acid, eicosapentaenoic acid (EPA; 20:5n-3). EPA can be elongated to docosapentaenoic acid (DPA 22:5n-3), which is further desaturated to docosahexaenoic acid (DHA; 22:6n-3). EPA and DHA are also precursors of several classes of eicosanoids and are known to play several other critical roles, some of which are discussed further below. The conversion from parent fatty acids into the LC PUFAs - EPA, DHA, and AA - appears to occur slowly in humans. In addition, the regulation of conversion is not well understood, although it is known that ALA and LA compete for entry into the metabolic pathways. Physiological Functions of EPA and AA As stated earlier, fatty acids play a variety of physiological roles. The specific biological functions of a fatty acid are determined by the number and position of double bonds and the length of the acyl chain. Both EPA (20:5n-3) and AA (20:4n-6) are precursors for the formation of a family of hormone- like agents called eicosanoids. Eicosanoids are rudimentary hormones or regulating - molecules that appear to occur in most forms of life. However, unlike endocrine hormones, which travel in the blood stream to exert their effects at distant sites, the eicosanoids are autocrine or paracrine factors, which exert their effects locally in the cells that synthesize them or adjacent cells. Processes affected include the movement of calcium and other substances into and out of cells, relaxation and contraction of muscles, inhibition and promotion of clotting, regulation of secretions including digestive juices and hormones, and control of fertility, cell division, and growth. 3 The eicosanoid family includes subgroups of substances known as prostaglandins, leukotrienes, and thromboxanes, among others. As shown in Figure 1.1, the long-chain omega-6 fatty acid, AA (20:4n-6), is the precursor of a group of eicosanoids that include series-2 prostaglandins and series-4 leukotrienes. The omega-3 fatty acid, EPA (20:5n-3), is the precursor to a group of eicosanoids that includes series-3 prostaglandins and series-5 leukotrienes. The AA-derived series-2 prostaglandins and series-4 leukotrienes are often synthesized in response to some emergency such as injury or stress, whereas the EPA-derived series-3 prostaglandins and series-5 leukotrienes appear to modulate the effects of the series-2 prostaglandins and series-4 leukotrienes (usually on the same target cells). More specifically, the series-3 prostaglandins are formed at a slower rate and work to attenuate the effects of excessive levels of series-2 prostaglandins. Thus, adequate production of the series-3 prostaglandins seems to protect against heart attack and stroke as well as certain inflammatory diseases like arthritis, lupus, and asthma. 3 EPA (22:6 n-3) also affects lipoprotein metabolism and decreases the production of substances including cytokines, interleukin 1ß (IL-1ß), and tumor necrosis factor a (TNF-a) 3

20 that have pro-inflammatory effects (such as stimulation of collagenase synthesis and the expression of adhesion molecules necessary for leukocyte extravasation [movement from the circulatory system into tissues]). 2 The mechanism responsible for the suppression of cytokine production by omega-3 LC PUFAs remains unknown, although suppression of omega-6-derived eicosanoid production by omega-3 fatty acids may be involved, because the omega-3 and omega- 6 fatty acids compete for a common enzyme in the eicosanoid synthetic pathway, delta-6 desaturase. DPA (22:5n-3) (the elongation product of EPA) and its metabolite DHA (22:6n-3) are frequently referred to as very long chain n-3 fatty acids (VLCFA). Along with AA, DHA is the major PUFA found in the brain and is thought to be important for brain development and function. Recent research has focused on this role and the effect of supplementing infant formula with DHA (since DHA is naturally present in breast milk but not in formula). Dietary Sources and Requirements Both ALA and LA are present in a variety of foods. LA is present in high concentrations in many commonly used oils, including safflower, sunflower, soy, and corn oil. ALA is present in some commonly used oils, including canola and soybean oil, and in some leafy green vegetables. Thus, the major dietary sources of ALA and LA are PUFA-rich vegetable oils. The proportion of LA to ALA as well as the proportion of those PUFAs to others varies considerably by the type of oil. With the exception of flaxseed, canola, and soybean oil, the ratio of LA to ALA in vegetable oils is at least 10 to 1. The ratios of LA to ALA for flaxseed, canola, and soy are approximately 1: 3.5, 2:1, and 8:1, respectively; however, flaxseed oil is not typically consumed in the North American diet. It is estimated that on average in the U.S., LA accounts for 89% of the total PUFAs consumed, and ALA accounts for 9%. Another estimate suggests that Americans consume 10 times more omega-6 than omega-3 fatty acids. 4 Table 1.2 shows the proportion of omega 3 fatty acids for a number of foods. 4

21 Figure 1.1. Classical omega-3 and omega-6 fatty acid synthesis pathways and the role of omega-3 fatty acid in regulating health/disease markers. Polyunsaturated Fatty Acids (PUFAs) Omega-6 Large intake (7-8% dietary energy)* Omega-3 Series-1 Prostaglandins: TXA 1 PGE 1 PGF 1a Linoleic acid (LA) 18:2 n-6 (Sunflower, soy, cottonseed, safflower oils) Delta-6 Desaturase (D6D) Minor intake ( % dietary energy)* *The dietary intake levels are based on approximate current levels in North American diets PGD 1 Gamma-linolenic acid (GLA) 18:3 n-6 (Evening primrose, borage, black currant oils) Alpha-Linolenic acid (ALA) 18:3 n-3 (Canola, Soybean, and Flaxseed oils, grains, green vegetables) Eicosanoids Series-2 Prostaglandins: TXA 2 PGE 2 PGF 2a PGD 2 PGH 2 PGL 2 Elongase Delta-6 Desaturase (D6D) Octadecatetranenoic acid 18:4 n-3 Series-4 Leukotrienes Series-3 Prostaglandins: PGE 3 PGH 3 PGI 3 TXA 3 Series-5 Leukotrienes Dihomo-gamma-linolenic acid (DGLA) 20:3 n-6 (Liver & other organ meats) Arachidonic acid (AA) 20:4 n-6 (Animal fats, brain, organ meats, egg yolk) Delta-5 desaturase (D5D) Elongase Eicosatetraenoic acid 20:4 n-3 Eicosapentaenoic acid (EPA) 20:5 n-3 (Fish liver oils, fish eggs) TNF-alpha IL-1 beta suppress amino acids DNA Thromboxanes (TX) are important for: - blood clotting - constricting blood vessels - inflammatory function of white blood cells Leukotrienes are important for: - inflammation - lung function Prostaglandins (PG) are important for: - pregnancy, birth - stomach function - kidney function - maintaining blood vessel patency - preventing blood clots - inflammation, response to infection Adrenic acid 22:4 n-6 Docosapentaenoic acid (DPA) 22:5 n-6 Docosapentaenoic acid (DPA) 22:5 n-3 24:4 n-6 24:5 n-3 24:5 n-6 24:6 n-3 Beta-oxidation Elongase Elongase D6D Beta-oxidation Docosahexaenoic acid (DHA) 22:6 n-3 (Human milk, egg yolks, fish liver oils, fish eggs, liver, brain, other organ meats) Lower VLDL, Apo B-100, Tg Extracellular Ca 2+ Endothelial and smooth muscle cells Adrenoceptors Cell membrane Intracellular Ca 2+ endoplasmic reticulum Energy metabolic pathway Beta-oxidation 5

22 Table 1.2. Sources and proportions of omega-3 fatty acids in common foods and supplements. Food/supplement EPA 20:5n-3 DHA 22:6n-3 DPA 22:5n-3 ALA 18:3n-3 Foods in which Total Omega-3 Fatty Acids account for more than 50% of Total PUFA Fish Anchovy U U U Halibut U U U Herring U U U Mackerel U U U U U U Salmon U U Sardine U Tuna U U Canned, U waterpacked U U Fresh Bluefin Oils/Supplements Cod liver oils Coromega * Fish oil capsules* Flaxseed/linseed oil* Herring oil MaxEPA* Menhaden oil Neuromins* Omacor* Ropufa* Salmon oil Sardine oil U U U U U U U U U U U U U U U U U U U U U U U U U U U U Seeds Flaxseeds/Linseeds Oils Foods/Supplements in which total Omega 3 fatty acids are 10-50% of total PUFA Black currant oil Canola oil** Mustard seed oils Soybean oil Walnut oil Wheat germ oil Other foods Wheat germ Human milk Foods/Supplements in which total Omega 3 fatty acids are less than 10% of total PUFA Efamol Marine* U U Soybeans Walnuts U U * Dietary Supplement ** Also called rapeseed oil U U U U U U U U U 6

23 Several lines of research have suggested that the high ratio of omega 6s to omega 3s currently consumed in the U.S. promotes a number of chronic diseases. 4 Because of the slow rate of elongation and further desaturation of the essential FA, the importance of LC PUFAs to many physiological processes, and the overwhelming ratio of omega 6s to omega 3s in the average U.S. diet, nutrition experts are increasingly recognizing the need for humans to augment the body s synthesis of omega 3 LC PUFAs by consuming foods that are rich in these compounds. According to data from two population-based surveys, the major dietary sources of LC omega-3 fatty acids in the U.S. population are fish, fish oil, vegetable oils (principally canola and soybean), walnuts, wheat germ, and some dietary supplements, and the primary dietary sources of omega-6 LC PUFAs are meats and dairy products. These surveys, the Continuing Food Survey of Intakes by Individuals (CSFII) and the third National Health and Nutrition Examination (NHANES III) surveys, are the main sources of dietary intake data for the U.S. population. The CSFII has the advantage of collecting dietary recall data over a period of several days, which may permit estimates of omega-3 intake that more accurately reflect individual intakes than do those of NHANES. However, NHANES intake data have the advantage of being able to be linked to health outcomes. Table 1.3 provides a list of food sources of omega-3 fatty acids. Table 1.3. Good food sources* of omega 3 fatty acids. EPA+DHA ALA EPA+DHA ALA Fish (3oz. Cooked) Oils (1 Tbs.) Anchovy U Canola U Halibut U Cod liver U Herring, Atlantic U Flaxseed/linseed U Pacific U Herring U Mackerel, Atlantic U Menhaden U Pacific U Salmon U Salmon, Atlantic** U Sardine U Sardines U Soybean U Trout, Rainbow U Walnut U Tuna, Albacore U Wheat germ U Canned light, water-packed Canned white, water-packed Fresh Bluefin U U U Organ Meats (3 oz. Cooked) Seeds Brain, lamb U Flaxseeds/linseeds (1 Tbs.) U Brain, pork U Thymus, calf U Other Foods Caviar (1 oz.)# U Human breast milk (1c)# U Soybeans, cooked (1/2c) U Tofu, regular (1/2c) U Walnuts (1/4c) U Wheat germ (1/4c)# U Source: Figures adapted from USDA, 2003; *Foods that provide (per serving) 10% or more of the Adequate Intake (AI) for ALA or the Acceptable Macronutrient Distribution Range (AMDR) for EPA and DHA (10% of the AMDR for ALA); an AI is a recommended average daily intake level based on observed or experimentally determined estimates of nutrient intake by a group of apparently healthy people (thus, assumed to be adequate) when an RDA cannot be determined; an AMDR is defined as a range of intakes for a particular energy source that is associated with reduced risk of chronic disease while providing adequate intake of essential nutrients. 5 # Standard serving size not established; **Farm-raised Atlantic salmon have nearly identical omega-3 fatty acid levels to wild Atlantic salmon and significantly more omega-3 fatty acids than wild Pacific salmon. 7